Investigating the Possible Interfering Effect of COX-2 Inhibitors on Antimalarial Activity of Mefloquine and Artesunate

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Wanna Chaijaroenkul
Jirawadee Tippayapornswan
Maethee Vichitnontakarn
Kesara Na-Bangchang


Cyclooxygenase (COX) is the key enzyme responsible for the production of prostanoids.  It plays important roles in the inflammatory process and pathogenesis of several diseases, including malaria. However, there has been no information of the inhibitory effects of COX inhibitors on inflammatory mediators and standard antimalarial drugs. Therefore, in this study, both selective and non-selective COX-2 inhibitors (aspirin, ibuprofen, piroxicam, and naproxen), alone or in combination, were investigated for their antimalarial activities in vitro. The antimalarial activity was assessed using the SYBR Green I fluorescent-based technique. For mefloquine- aspirin combination, the test wells consisted of mefloquine and aspirin at the ratios of 200:0, 140:30000, 100:50000, 60:70000, and 0:100000 nM. The concentration ratios for artesunate-aspirin were 50:0, 35:30000, 25:50000, 15:70000, and 0:100000 nM. The median (range) concentrations that inhibited parasite growth by 50% (IC50) of aspirin for K1 and 3D7 clones were 1,889 (1,600-2,792) and 2,417 (912-2,630) nM, respectively. The corresponding values of mefloquine were 10.1 (8.1-13.9) and 23.4 (22.9-24.7) nM, respectively. The corresponding values of artesunate were 2.5 (1.6-3.4) vs. 2.2 (1.2-3.2) nM, respectively. The corresponding values for mefloquine were 10 (8-14) and 23 (23-25) nM, respectively. The corresponding values for artesunate were 2.5 (2-3) vs. 2 (1-3) nM, respectively. The IC50 values of ibuprofen, piroxicam and naproxen were higher than 100,000 nM for both clones. The median (range) sum fractional inhibitory concentrations (FIC) of mefloquine-aspirin interaction for K1 and 3D7 P. falciparum clones were 0.82 (0.79-1.0) and 0.97 (0.83-1.1), respectively. The corresponding sum FICs of artesunate-aspirin were 0.94 (0.88-0.95) and 0.95 (0.92-0.97), respectively. Results indicate indifferent antimalarial interaction between these two drugs when used in combination. 


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Research Articles
Author Biography

Wanna Chaijaroenkul, Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), Pathumthani, Thailand

Research Publications

  1. Thongdee P, Chaijaroenkul W, Kuesap J, Na-Bangchang K. Nested-PCR and a new ELISA-based NovaLisa test kit for malaria diagnosis in an endemic area of Thailand. Korean J Parasitol. 2014 Aug;52(4):377-81.
  2. Sumsakul W, Plengsuriyakarn T, Chaijaroenkul W, Viyanant V, Karbwang J, Na-Bangchang K. Antimalarial activity of plumbagin in vitro and in animal models. BMC Complement Altern Med. 2014;14(1):15.
  3. Phompradit P, Muhamad P, Wisedpanichkij R, Chaijaroenkul W, Na-Bangchang K. Four years' monitoring of in vitro sensitivity and candidate molecular markers of resistance of Plasmodium falciparum to artesunate-mefloquine combination in the Thai-Myanmar border. Malar J. 2014;13(1):23.
  4. Phompradit P, Muhamad P, Chaijaroenkul W, Na-Bangchang K. Genetic polymorphisms of candidate markers and in vitro susceptibility of Plasmodium falciparum isolates from Thai-Myanmar border in relation to clinical response to artesunate-mefloquine combination. Acta Trop. 2014 Jul 5;139C:77-83.
  5. Kuesap J, Chaijaroenkul W, Ketprathum K, Tattiyapong P, Na-Bangchang K. Evolution of genetic polymorphisms of Plasmodium falciparum merozoite surface protein (PfMSP) in Thailand. Korean J Parasitol. 2014 Feb;52(1):105-9.
  6. Chaijaroenkul W, Thiengsusuk A, Rungsihirunrat K, Ward SA, Na-Bangchang K. Proteomics analysis of antimalarial targets of Garcinia mangostana Linn. Asian Pac J Trop Biomed. 2014 Jul;4(7):515-9.
  7. Chaijaroenkul W, Mubaraki M, Ward SA, Na-Bangchang K. Metabolite footprinting of Plasmodium falciparum following exposure to Garcinia mangostana Linn. crude extract. Exp Parasitol. 2014 Aug 4.
  8. Bunyong R, Chaijaroenkul W, Plengsuriyakarn T, Na-Bangchang K. Antimalarial activity and toxicity of Garcinia mangostana Linn. Asian Pac J Trop Med. 2014 Sep;7(9):693-8.
  9. Thiengsusuk A, Chaijaroenkul W, Na-Bangchang K. Antimalarial activities of medicinal plants and herbal formulations used in Thai traditional medicine. Parasitol Res. 2013 Apr;112(4):1475-81.
  10. Rungsihirunrat K, Kuesap J, Chaijaroenkul W, Na Bangchang K. Distribution and Emergence of Chloroquine-Resistant Plasmodium Vivax. J Health Res. 2013;27(1):57-65.
  11. Na-Bangchang K, Muhamad P, Ruaengweerayut R, Chaijaroenkul W, Karbwang J. Identification of resistance of Plasmodium falciparum to artesunate-mefloquine combination in an area along the Thai-Myanmar border: integration of clinico-parasitological response, systemic drug exposure, and in vitro parasite sensitivity. Malar J. 2013;12:263.
  12. Muhamad P, Chaijaroenkul W, Phompradit P, Rueangweerayut R, Tippawangkosol P, Na-Bangchang K. Polymorphic patterns of pfcrt and pfmdr1 in Plasmodium falciparum isolates along the Thai-Myanmar border. Asian Pac J Trop Biomed. 2013 Dec;3(12):931-5.
  13. Rungsihirunrat K, Chaijaroenkul W, Siripoon N, Seugorn A, Thaithong S, Na-Bangchang K. Comparison of protein patterns between Plasmodium falciparum mutant clone T9/94-M1-1(b3) induced by pyrimethamine and the original parent clone T9/94. Asian Pacific Journal of Tropical Biomedicine. 2012;2(1):66-9.
  14. Plengsuriyakarn T, Viyanant V, Eursitthichai V, Tesana S, Chaijaroenkul W, Itharat A, et al. Cytotoxicity, toxicity, and anticancer activity of Zingiber officinale Roscoe against cholangiocarcinoma. Asian Pac J Cancer Prev. 2012;13(9):4597-606.
  15. Pacharapruethipakorn N, Chaijaroenkul W, Na Bangchang K, Itharat A, Aunpad R. Screenings Test of Traditional Medicinal Herbs for Bactericidal Activity and Their Effects Determination. J Health Res. 2012;26.
  16. Wisedpanichkij R, Grams R, Chaijaroenkul W, Na-Bangchang K. Confutation of the existence of sequence-conserved cytochrome P450 enzymes in Plasmodium falciparum. Acta Trop. 2011 Jul;119(1):19-22.
  17. Sriwanitchrak P, Viyanant V, Chaijaroenkul W, Srivatanakul P, Gram HR, Eursiddhichai V, et al. Proteomics analysis and evaluation of biomarkers for detection of cholangiocarcinoma. Asian Pac J Cancer Prev. 2011;12(6):1503-10.
  18. Rungsihirunrat K, Chaijaroenkul W, Siripoon N, Seugorn A, Na-Bangchang K. Genotyping of polymorphic marker (MSP3alpha and MSP3beta) genes of Plasmodium vivax field isolates from malaria endemic of Thailand. Trop Med Int Health. 2011 Mar 29;16(7):794-801.
  19. Phompradit P, Wisedpanichkij R, Muhamad P, Chaijaroenkul W, Na-Bangchang K. Molecular analysis of pfatp6 and pfmdr1 polymorphisms and their association with in vitro sensitivity in Plasmodium falciparum isolates from the Thai-Myanmar border. Acta Trop. 2011 Oct-Nov;120(1-2):130-5.
  20. Phompradit P, Kuesap J, Chaijaroenkul W, Rueangweerayut R, Hongkaew Y, Yamnuan R, et al. Prevalence and distribution of glucose-6-phosphate dehydrogenase (G6PD) variants in Thai and Burmese populations in malaria endemic areas of Thailand. Malar J. 2011 Dec 15;10(1):368.
  21. Muhamad P, Ruengweerayut R, Chacharoenkul W, Rungsihirunrat K, Na-Bangchang K. Monitoring of clinical efficacy and in vitro sensitivity of Plasmodium vivax to chloroquine in area along Thai Myanmar border during 2009-2010. Malar J. 2011;10(1):44.
  22. Muhamad P, Phompradit P, Sornjai W, Maensathian T, Chaijaroenkul W, Rueangweerayut R, et al. Polymorphisms of Molecular Markers of Antimalarial Drug Resistance and Relationship with Artesunate-Mefloquine Combination Therapy in Patients with Uncomplicated Plasmodium falciparum Malaria in Thailand. Am J Trop Med Hyg. 2011 Sep;85(3):568-72.
  23. Muhamad P, Chaijaroenkul W, Congpuong K, Na-Bangchang K. SYBR Green I and TaqMan quantitative real-time polymerase chain reaction methods for the determination of amplification of Plasmodium falciparum multidrug resistance-1 gene (pfmdr1). J Parasitol. 2011 Oct;97(5):939-42.
  24. Muhamad P, Chaijareonkul W, Rungsihirunrat K, Ruengweerayut R, Na Bangchang K. Assessment of in vitro sensitivity of Plasmodium vivax fresh isolates. Asian Pacific Journal of Tropical Biomedicine. 2011:49-53.
  25. Chaijaroenkul W, Wongchai T, Ruangweerayut R, Na-Bangchang K. Evaluation of Rapid Diagnostics for Plasmodium falciparum and P. vivax in Mae Sot Malaria Endemic Area, Thailand. Korean J Parasitol. 2011 Mar;49(1):33-8.
  26. Chaijaroenkul W, Ward SA, Mungthin M, Johnson D, Owen A, Bray PG, et al. Sequence and gene expression of chloroquine resistance transporter (pfcrt) in the association of in vitro drugs resistance of Plasmodium falciparum. Malar J. 2011;10(1):42.
  27. Chaijaroenkul W, Viyanant V, Mahavorasirikul W, Na-Bangchang K. Cytotoxic Activity of Artemisinin Derivatives Against Cholangiocarcinoma (CL-6) and Hepatocarcinoma (Hep-G2) Cell Lines. Asian Pac J Cancer Prev. 2011;12(1):55-9.
  28. Chaijaroenkul W, Rungsihirunrat K, Na-Bangchang K. Metabolomics approaches in parasitology. J Health Res. 2011;25(1):25-33.
  29. Wisedpanichkij R, Chaijareonkul W, Muhamad P, Prompradit P, Na Bangchang K. Polymorphisms of the oxidant enzymes glutathione S-transferase and glutathione reductase and their association with resistance of Plasmodium falciparum isolates to antimalarial drugs. Asian Pacific J Trop Med. 2010;3(9):673-7.
  30. Wisedpanichkij R, Chaijareonkul W, Muhamad P, Na Bangchang K. Investigation of the association between prostaglandin D2 (PGD2) levels and malaria pathogenicity and severity J Health Res. 2010;26(4):143-9.
  31. Na-Bangchang K, Ruengweerayut R, Mahamad P, Ruengweerayut K, Chaijaroenkul W. Declining in efficacy of a three-day combination regimen of mefloquine-artesunate in a multi-drug resistance area along the Thai-Myanmar border. Malar J. 2010;9:273.
  32. Mungthin M, Suwandittakul N, Chaijaroenkul W, Rungsrihirunrat K, Harnyuttanakorn P, Seugorn A, et al. The patterns of mutation and amplification of Plasmodium falciparum pfcrt and pfmdr1 genes in Thailand during the year 1988 to 2003. Parasitol Res. 2010 Aug;107(3):539-45.
  33. Mahavorasirikul W, Viyanant V, Chaijaroenkul W, Itharat A, Na-Bangchang K. Cytotoxic activity of Thai medicinal plants against human cholangiocarcinoma, laryngeal and hepatocarcinoma cells in vitro. BMC Complement Altern Med. 2010;10:55.
  34. Chaijaroenkul W, Wisedpanichkij R, Na-Bangchang K. Monitoring of in vitro susceptibilities and molecular markers of resistance of Plasmodium falciparum isolates from Thai-Myanmar border to chloroquine, quinine, mefloquine and artesunate. Acta Trop. 2010 Feb;113(2):190-4.
  35. Wisedpanichkij R, Chaijaroenkul W, Sangsuwan P, Tantisawat J, Boonprasert K, Na-Bangchang K. In vitro antimalarial interactions between mefloquine and cytochrome P450 inhibitors. Acta Trop. 2009 Oct;112(1):12-5.
  36. Suwandittakul N, Chaijaroenkul W, Harnyuttanakorn P, Mungthin M, Na Bangchang K. Drug resistance and in vitro susceptibility of Plasmodium falciparum in Thailand during 1988-2003. Korean J Parasitol. 2009 Jun;47(2):139-44.
  37. Rungsihirunrat K, Chaijaroenkul W, Seugorn A, Na-Bangchang K, Thaithong S. Association between chloroquine resistance phenotypes and point mutations in pfcrt and pfmdr1 in Plasmodium falciparum isolates from Thailand. Acta Trop. 2009 Jan;109(1):37-40.
  38. Aunpad R, Somsri S, Na-Bangchang K, Udomsangpetch R, Mungthin M, Adisakwattana P, et al. The effect of mimicking febrile temperature and drug stress on malarial development. Ann Clin Microbiol Antimicrob. 2009;8:19.
  39. Chaijaroenkul W, Pruktal P, Muhamad P, Na-Bangchang K. Assessment of in vitro antimalarial interactions between dihydroartemisinin and fosmidomycin. Southeast Asian J Trop Med Public Health. 2007 Sep;38(5):791-5.
  40. Chaijaroenkul W, Tippawangkosol P, Kuesap J, Congpuong K, Ruenweerayut R, Suwandittakul N, et al. Comparison of two in vitro sensitivity tests for Plasmodium falciparum. Southeast Asian J Trop Med Public Health. 2006 Jan;37(1):5-12.
  41. Chaijaroenkul W, Bangchang KN, Mungthin M, Ward SA. In vitro antimalarial drug susceptibility in Thai border areas from 1998-2003. Malar J. 2005;4:37.


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